DESCRIPTION, OVERALL (provided by applicant): A complex interaction of different processes play a critical role in the development of hematopoietic lineages, and among the most important are the controls of hematopoietic stem cell (HSC) commitment. Understanding this process is critical to understanding HSC function as well as self-renewal, and this understanding will lead to novel insights into manipulation of HSC for therapeutic purposes, as well as understanding disease processes which involve HSC, including leukemia. Finally, advances in understanding HSC commitment will serve as a model for understanding other types of stem cells. This program, Hematopoietic Stem Cell Commitment, consists of 4 projects, all of which are interrelated and focused on understanding some aspect of HSC regulation and function. They include: Project 1: Branching points of hematopoietic stem cell commitment, (Project Leader: Koichi Akashi, Dana Farber Cancer Institute, Harvard Medical School; Project 2, Signal Transduction Mechanisms in Hematopoietic Stem Cells (Project Leader: Roger J. Davis, University of Massachusetts Medical Center, Worcester); Project 3: Runx1 in hematopoietic stem cells (Project Leader: Dong-Er Zhang, Scripps Research Institute); and Project 4, Regulation of C/EBP alpha in hematopoiesis (Project Leader: Daniel G. Tenen, Beth Israel Deaconess Medical Center, Harvard Medical School). The administrative core will be responsible for many interactive functions of the program, including regular meetings, seminars, and communication among projects. A Biostatistics Core will provide direction with statistical design and analysis. PUBLIC HEALTH RELEVANCE: By combining a variety of approaches, including studies of transcriptional regulation, signal transduction, and knockout and knockin mice, we will provide valuable new information concerning the regulation of stem cell function.